The goal of the proposed research is to identify and characterize novel genes in vivo which contribute to viral persistence. Utilizing forward genetics, we will phenotypically identify and subsequently characterize mutant mice in which an otherwise persistent viral infection is rapidly cleared. This approach will enable us to uncover novel therapeutic targets for persistent viral infections which may also be applied to cancer and various immune disorders. Obtaining mutant mice resistant to persistent viral infection will provide the candidate and the scientific community powerful resources to investigate these issues in vivo for many years. As a physician scientist, I am uniquely trained to understand the most important questions in human disease as well as the most powerful methods to advance our understanding of these critical issues. I have a clinical background in internal medicine with specialty training in Dermatology. Scientifically, my graduate training has given me an extensive knowledge base in immunology with a focus in viral pathogenesis. During this time, I formed international collaborations to further our understanding of herpesvirus infection of macrophages. As a result of this work and my medical training, I have learned how to fully utilize my environment regarding both staff and resources in the clinic and laboratory. By overseeing and utilizing staff and resources in both environments, I have been a part of many projects to further biomedical research and ultimately advance patient care. These collaborative efforts have resulted in several peer-reviewed publications. This training and collaborative spirit has been extended in my post-doctoral career. I sought out Drs. Oldstone and Beutler to form a unique collaboration combining the great strengths of both labs. This has already resulted in several manuscripts in preparation as well as the foundation for my independent career in academic biomedical research. I have setup a novel in vivo genetic screen to characterize and better understand one of the most critical questions in viral pathogenesis: "What are the pathways involved in viral persistence versus clearance?" The Scripps Research Institute provides a great opportunity for myself, a physician scientist, to further my knowledge base and apply this knowledge to focused research projects. Specifically, there are numerous talks from world-renown investigators every week in our Immunology building as well as adjacent buildings. These and other activities lead to new ideas and collaborations. On a daily basis I discuss these ideas with my colleagues and possible avenues of explorations based on findings of our own and others. The summation of my research proposal, mentors and environment will give me the opportunity to obtain both my immediate and long-term career goals. I will expand my knowledge base and apply it in this rich environment to publish important and relevant findings. During this process, I will continue to develop enduring scientific partnerships-one of the richest aspects of my scientific career, and critical to my scientific future. I look forward to expanding and furthering these efforts in academic biomedical research as I continue my journey to ultimately be a professor, making significant contributions at a leading academic research center. Project Narrative: Persistent viral infections such as HIV, HepB and HepC represent a large economic and humanitarian burden. By identifying the host genes conferring resistance, we seek to better understand the pathways and thus therapeutic targets for persistent viral infections.